rs1057516055

Variant names:

• chrM-1661-A-G
• rs1057516055
• unassigned_transcript_4786:c.60A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PS4_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The m.1661A>G variant in MT-TV has been reported in two unrelated families (PS4_supporting). Limited phenotypic details are provided in the first reported family (Patient 6 in Bacalhau et al., 2017, PMID:28027978) however a subsequent publication reported the proband in this family had seizures, hypotonia, developmental delay, elevated blood lactate, and combined deficiency of electron transport chain enzyme activities (PMID:32715519). The heteroplasmy level and information on family members and/or testing in family members were not reported in this first kindred. The second family reported was a large kindred from the Venezuelan Andes with axonal Charcot-Marie-Tooth (CMT) disease (motor and sensory neuropathy). Muscle weakness, muscle atrophy, and ataxia were also seen in the affected individuals in this family (Fay et al., 2020, PMID:32715519). Muscle biopsies performed in several individuals showed denervation and reinnervation, in addition to mitochondrial hyperplasia, mildly increased glycogen, and the presence of mitochondrial crystalline arrays. Combined respiratory chain enzyme deficiencies were also seen in affected individuals from this kindred. The variant was present at homoplasmy in blood and/or muscle in both affected and unaffected individuals from this kindred. There are no reported de novo occurrences on this variant to our knowledge. The computational predictor MitoTIP suggests this variant is benign (27.6 percentile; BP4).This variant is present in population databases (MITOMAP: 1/61,168 sequences, AF=0.002%, haplogroup (Hg) H1c; Helix: 2/195,983 (0.001%), also 19 heteroplasmic occurrences, homoplasmic occurrences in Hg I and V, heteroplasmic in multiple haplogroups; and gnomAD v3.1.2: 2/56,398 (0.004%), also three heteroplasmic occurrences (heteroplasmy levels: 10-20%; 20-30%; 90-100%), one in Hg T, one in H, one in B, one in K, one in L3). Given the frequency of this variant, it does not meet PM2 criterion. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, BP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA16040644/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: TRNV unassigned_transcript_4786 synonymous
• Scores: Mitotip Uncertain 9.1
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:4 Charcot-Marie-Tooth-(CMT)
• Conservation: PhyloP100: 0.0530
• Publications: 0 publications found

Genes affected

TRNV (HGNC:7500): (mitochondrially encoded tRNA valine)

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387342.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TV	ENST00000387342.1	TSL:6	n.60A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-RNR2	ENST00000387347.2	TSL:6	n.-10A>G		upstream_gene	N/A
	MT-RNR1	ENST00000389680.2	TSL:6	n.*60A>G		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0 AC: 1

Gnomad homoplasmic AF: 0.000035 AC: 2 AN: 56398

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56398

Mitomap

Disease(s): Charcot-Marie-Tooth-(CMT)

Status: Reported-[VUS]

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1 (2)
-	1	-	Epilepsy;C0424605:Developmental delay;C1853743:Axial hypotonia;CN239816:Hyperlactaemia (1)
-	1	-	Mitochondrial disease (1)
-	1	-	not specified (1)
1	-	-	Spastic paraplegia, mitochondrial (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	9.1
Hmtvar	Benign	0.0
PhyloP100		0.053

Other links and lift over

dbSNP: rs1057516055; hg19: chrM-1663;